Petra E. Spies

Cerebrospinal fluid alpha-synuclein does not discriminate between dementia disorders.

Alpha-synuclein is the major constituent of Lewy bodies found in neurons in dementia with Lewy bodies (DLB) and might be of diagnostic value as a biomarker for DLB. We hypothesized that, as a consequence of increased accumulation of alpha-synuclein intraneuronally in DLB, the levels of alpha-synuclein in cerebrospinal fluid (CSF) of DLB patients would be lower than in other dementias. Our objective was to investigate the CSF levels of alpha-synuclein in several dementia disorders compared to control levels and to investigate the diagnostic value of CSF alpha-synuclein as a marker to discriminate between DLB and other types of dementia. We analyzed the levels of alpha-synuclein in CSF of 40 DLB patients, 131 patients with Alzheimers disease, 28 patients with vascular dementia, and 39 patients with frontotemporal dementia. We did not find any significant differences in CSF alpha-synuclein levels between DLB patients and patients with Alzheimers disease, vascular dementia or frontotemporal dementia. We conclude that in clinically diagnosed patients, alpha-synuclein does not appear to be a useful biomarker for the differentiation between DLB and other types of dementia.

Hourly variability of cerebrospinal fluid biomarkers in Alzheimer's disease subjects and healthy older volunteers.

Large hour-to-hour variability has previously been demonstrated in the cerebrospinal fluid (CSF) concentrations of Alzheimers disease (AD) biomarkers amyloid β(42) (Aβ(42)) and Aβ(40) in healthy younger subjects. We investigated the within-subject variability over 36 hours in CSF Aβ and tau proteins, in older subjects and AD patients. Six patients with mild stage AD (59-85 years, Mini Mental State Examination (MMSE) 16-26) and 6 healthy older volunteers (64-77 years) received an intrathecal catheter from which, during 36 hours, each hour 6 mL of CSF was drawn. Concentrations of Aβ(42), Aβ(40), total tau, and phosphorylated tau were determined and the variability was analyzed. Within-subject variability within 3-hour periods was assessed as the coefficient of variation, which was comparable for these 4 biomarkers in controls (4.2%-4.6%) and AD (3.1%-5.8%). Variability over 12 hour periods was 5.3% to 9.5%. These findings suggest that CSF biomarker variability is relatively low in healthy older controls and AD patients. Furthermore, continuous sampling of CSF proved to be a useful and robust method, which may also be used to investigate AD pathogenesis and to evaluate pharmacotherapeutic interventions.

CSF α-synuclein concentrations do not fluctuate over hours and are not correlated to amyloid β in humans.

Reports on the value of cerebrospinal fluid (CSF) α-synuclein as a biomarker for dementia with Lewy bodies and Parkinson disease are contradicting. This may be explained by fluctuating CSF α-synuclein concentrations over time. Such fluctuations have been suggested for CSF amyloid β concentrations. Furthermore, a physiological relationship between α-synuclein and amyloid β has been suggested based on in vitro research. We performed repeated CSF sampling in healthy elderly and AD patients and showed that sinusoidal fluctuations in CSF α-synuclein concentrations were not present. Furthermore, we did not find evidence for an interaction between amyloid β and α-synuclein concentrations in CSF.

Experiences with cerebrospinal fluid analysis in Dutch memory clinics

Background:  Evidence on cerebrospinal fluid (CSF) analysis to demonstrate Alzheimer’s disease has not yet been implemented in diagnostic guidelines.

Cerebrospinal Fluid Biomarkers in Diagnosing Alzheimer's Disease in Clinical Practice: An Illustration with 3 Case Reports.

Analysis of the brain specific biomarkers amyloid β42 (Aβ42) and total tau (t-tau) protein in cerebrospinal fluid (CSF) has a sensitivity and specificity of more than 85% for differentiating Alzheimer’s Disease (AD) from non-demented controls. International guidelines are contradictory in their advice on the use of CSF biomarkers in AD diagnostics, resulting in a lack of consistency in clinical practice. We present three case reports that illustrate clinical practice according to the Dutch and European guidelines and portray the value of CSF biomarker analysis as an add-on diagnostic to the standard diagnostic workup for AD.

Elderly: A Term to Avoid or to Embrace?

Spies, Petra E Claassen, Jurgen A H R United States J Am Geriatr Soc. 2011 Oct;59(10):1986-7. doi: 10.1111/j.1532-5415.2011.03610_17.x.

CEREBROSPINAL FLUID BIOMARKERS IN ALZHEIMER'S DISEASE: ARE THE HYPOTHESES MORE DYNAMIC THAN THE BIOMARKERS?

ACKNOWLEDGMENTS Conflict of Interest: Funding provided by Allergan, LLC. Staskin: Received honorarium from and consultant for Allergan, Astella, Pfizer, and Watson; speakers’ forum at Allergen, Astella, and Pfizer. Kay: Consultant for Allergan on study design, test administration, evaluation of CNS effects of antimuscarinics, and publications; received honoraria for consulting and training speakers. Consultant and speaker for Pfizer, Novartis. Consultant for Watson. Tannenbaum: Speaker and consultant for Allergan. Goldman: speaker for Pfizer, Astellas, Novartis, and Watson; consultant for Johnson and Johnson, Pfizer, and Allergan; investigator for Allergan. Bhashi and Ling: employees of Allergan, LLC, Pharmacology. Oefelein: employee of Allergan, LLC, Urology. Author Contributions: Staskin: study concept and design, analysis and interpretation of data, preparation of manuscript. Kay: study design, training of site staff to administer memory tests, quality assurance of collected data, interpretation of results, development of manuscript. Tannenbaum: analysis and interpretation of data, preparation of manuscript. Goldman: study design, data analysis, manuscript preparation. Oefelein: study design, conduct, monitoring, analysis of data, manuscript preparation. Bashsi and Ling: pharmacokinetics, bioanalytics, preparation of manuscript. Sponsor’s Role: None. REFERENCES

Cerebrospinal Fluid Tau and Amyloid β Proteins Do Not Correlate With Cognitive Functioning in Cognitively Impaired Memory Clinic Patients

Objective: The aim of this study was to investigate the influence of cerebrospinal fluid (CSF), amyloid b42 (Ab42), phosphorylated tau181 (p-tau), and total tau (t-tau) on cognitive functioning. Methods: We analyzed the ability of the CSF biomarkers Ab42, p-tau, and t-tau to predict the results on the Cambridge Cognitive Examination–Revised (CAMCOG-R), a cognitive screening test that assesses multiple cognitive domains, in 65 memory clinic patients (73.1±8.2 years) (n=30 probable Alzheimer’s disease [AD], n=7 possible AD, n=12 non-AD dementia, n=16 mild cognitive impairment). Results: We found no correlations between CSF biomarkers and CAMCOG-R performance in the whole group, nor in subgroups based on aberrant biomarker concentrations. Discussion: Changed concentrations of CSF amyloid b42, p-tau, and t-tau cannot be directly linked to cognitive function in our sample of patients with cognitive impairment. Possibly, compensatory mechanisms such as cognitive reserve determine cognitive performance, rather than the absolute amount of damage caused by Ab deposition and tangle formation. In addition, abnormal CSF biomarker concentrations may not be a direct reflection of the amount of neuronal damage, but merely serve as an indicator of AD pathology. Conclusion: While CSF biomarkers are valuable in establishing AD pathology, they cannot be used to predict severity of cognitive impairment.

Cerebrospinal fluid alpha-synuclein does not discriminate between dementia disorders

(p<0.01). The Ab42/Ab40 ratio was significantly lower in AD patients than in all other groups (p <0.001). Differentiating AD from VaD, DLB and nonAD improved when the Ab42/Ab40 ratio was used instead of Ab42 concentrations alone (p 0.005). Conclusions: In clinically diagnosed patients with dementia the CSF Ab42/Ab40 ratio improves differentiation of AD patients from VaD, DLB and non-AD patients, when compared to Ab42 alone.

Hourly variability of cerebrospinal fluid biomarkers in Alzheimer patients and healthy elderly controls

Diane Slats, Petra E. Spies, Jurgen A. H. R. Claassen, Magnus J. C. Sjögren, Jack Tseng, Marcel M. Verbeek, Marcel G. M. Olde Rikkert, Radboud University Nijmegen Medical Centre, Department of Geriatric Medicine 925, Nijmegen, Netherlands; Alzheimer Centre Nijmegen, Nijmegen, Netherlands; Radboud University Nijmegen Medical Centre, Department of Geriatric Medicine, Nijmegen, Netherlands; Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands; Merk-Schering-Plough Research Institute, Oss, Netherlands; Merck-Schering-Plough Research Institute, Kenilworth, NY, USA; Radboud University Nijmegen Medical Centre, Department of Laboratory Medicine, Nijmegen, Netherlands. Contact e-mail: d.slats@ger.umcn.nl